Laboratory for Structural Bioinformatics

Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all the partners required for sumoylation. Ubc9 has been implicated in a variety of human malignancies. In order to exploit the therapeutic potential of Ubc9, we have identified the potential site to target for rational drug design using molecular modeling approaches. The structural information derived was then used to prioritize hits from a small molecule library for biological assay using a virtual screening protocol which involves shape matching with known inhibitor and docking of a small molecule library utilizing computational approaches that incorporate both ligand and protein flexibility. Nineteen compounds were acquired from different chemical vendors and were tested for Ubc9 inhibitory activities. Five compounds showed inhibitory activity against Ubc9 out of which one compound was selected for further optimization. Similarity search was then carried out to retrieve commercially available derivatives, which were further acquired and assayed that resulted in two compounds with acceptable potency. These two compounds can be used as starting points for the development of more potent inhibitors of Ubc9 targeting the predicted site. This work has been published in JCIM (publication).

Our paper has been selected as the cover for the October issue.